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Journal )JCBN the 1880-5086 0912-0009 Kyoto, Original 10.3164/jcbn.11-75 jcbn11-75 Society Japan of Article Clinical for Free Biochemistry Radical Research and Nutrition Japan Different gastoroesophageal reflux symptoms of middle aged to elderly asthma and chronic obstructive pulmonary disease (COPD) patients Yasuo Shimizu,1,2,3,* Kunio Dobashi,4 Motoyasu Kusano1 and Masatomo Mori1
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3 39 15 Showa machi, Maebashi, Gunma 371 8511, Japan Jobu Hospital for Respiratory Disease, 586 1 Taguchi machi, Maebashi, Gunma 371 0048, Japan 3 Department of Pulmonary Medicine, Maebashi Red Cross Hospital, 3 21 36 Asahi cho Maebashi, Gunma 371 0014, Japan 4 Gunma University School of Health Sciences, 3 39 15 Showa machi, Maebashi, Gunma 371 8511, Japan (Received 24 May, 2011; Accepted 6 July, 2011; Published online 11 November, 2011) ??
Symptomatic differences and reproduction the impact under of any gastroesophageal Creative stricted vided Copyright This 200? the is use, original an Commons open distribution, © 200? work access JCBN Attribution isarticle and properly distributed License, cited. which in the permits medium, terms of unreprothe reflux disease (GERD) have not been clarified in patients with asthma and chronic obstructive pulmonary disease (COPD). The purpose of this study is to assess the differences of GERD symp toms among asthma, COPD, and disease control patients, and determine the impact of GERD symptoms on exacerbation of asthma or COPD by using a new questionnaire for GERD. A total of 120 subjects underwent assessment with the frequency scale for the symptoms of GERD (FSSG) questionnaire, including 40 age matched patients in each of the asthma, COPD, and disease control groups. Asthma and control patients had more regurgitation related symptoms than COPD patients (p<0.05), while COPD patients had more dysmotility related symptoms than asthma patients (p<0.01) or disease control patients (p<0.01). The most distinctive symptom of asthma patients with GERD was an unusual sensation in the throat, while bloated stomach was the chief symptom of COPD patients with GERD, and these symptoms were associated with disease exacerbations. The presence of GERD diagnosed by the total score of FSSG influences the exacer bation of COPD. GERD symptoms differed between asthma and COPD patients, and the presence of GERD diagnosed by the FSSG influences the exacerbation of COPD. Key Words: GERD, asthma, COPD, FSSG, dismotility
matched asthma and COPD patients with GERD diagnosed by the FSSG. The aims of this study were to compare the prevalence of GERD and the symptoms of GERD among asthma, COPD, and disease control patients. The impact of GERD (evaluated by the FSSG) on exacerbation of asthma and COPD was also examined. Subjects and Methods
Subjects. A total of 120 subjects underwent the FSSG, including 40 patients with asthma, 40 patients with COPD, and 40 disease control subjects without asthma or COPD. The characteristics of the subjects enrolled in this study are shown in Table 1. The diagnosis of asthma was established according to the Global Initiative for Asthma report (GINA),(14) as described previously,(4) while a diagnosis of COPD was established according to the Global Initiative for Chronic obstructive Lung disease report (GOLD).(15) The disease control patients had hypertension (n = 26), hyperlipidemia (n = 11), insomnia (n = 1), prostatomegaly (n = 1), and cervical spondylosis (n = 1) without respiratory symptoms and without receiving respiratory medications. Patients were excluded if they had a history of esophageal, gastric, or duodenal surgery, were using acid-suppressing drugs of PPI, H2 receptor antagonist or gastroprokinetic agents such as selective serotonin (5HT4) agonists, were mentally incompetent, or were being treated with an angiotensin-converting enzyme (ACE) inhibitor. Since COPD occurs rather older than young, less than 50 years old were excluded. Protocol. This study is retrospective cohort-study. Pulmonary function tests [% vital capacity (% VC), forced vital capacity (FVC), and forced expiratory volume in 1 sec (FEV1.0)] were measured with a CHESTAC −55V (CHEST MI, Tokyo, Japan) at Gunma University and with a CHESTAC −5500 or −8800 (CHEST MI, Tokyo, Japan) at Jobu Hospital. Pulmonary function in disease control was not measured because this study is retrospective study and measuring pulmonary function was not approved by institute committee. Sputum was obtained after inhaling 3 ml of 3% saline via a nebulizer, and cells were counted. If a patient could not expectorate the sputum, 3 ml of 6% saline were nebulized repeatedly. Defimition of adequate sputum was one in which there were fewer than 20% squamous cells and where viability was <50%.(16) The eosinophil count was determined by Hansel stain.(17) For calculation of the dose of inhaled steroid, fluticasone was assumed to be about twice the strength of
*To whom correspondence should be addressed. E mail: firstname.lastname@example.org u.ac.jp
GIntroduction astroesophageal reflux (GER) is a potential trigger for supraesophageal manifestations of asthma and chronic obstructive pulmonary disease (COPD).(1,2) The prevalance of gastroesophageal reflux disease (GERD) in asthma patients was 42% to 69% according to the questionnaire for the diagnosis of reflux disease (QUEST).(3,4) In COPD patients, the prevalance was 37% according to the Mayo clinic GERD questionnaire.(5,6) GER is common in patients with pulmonary disease and is involved in the pathophysiology of exacerbation of asthma and COPD, but proton pump inhibitors (PPIs) show limited efficacy for improvement of pulmonary function and respiratory symptoms in asthma or COPD patients with GERD.(7–9) Failure of PPI therapy is observed in patients who are diagnosed as having GERD by endoscopy, pH testing and esophageal impedance.(10) Therefore, another mechanism that has attracted attention is gastric motor activity.(11) In contrast, QUEST covers more typical symptoms of acid regurgitation, the frequency scale for the symptoms of GERD (FSSG) is a recently developed questionnaire that covers 12 symptoms, including not only typical regurgitation symptoms such as “heartburn” but also dysmotility symptoms such as “heavy stomach”.(12) GERD also changes with age,(13) and there have been no reports about the prevalance and features of GERD symptoms in age-
doi: 10.3164/jcbn.11 75 ©2012 JCBN
J. Clin. Biochem. Nutr. | March 2012 | vol. 50 | no. 2 | 169–175
19) The FSSG has been proven to be a useful questionnaire for the assessment of GERD. This study was conducted according to the Declaration of Helsinki.0* 0.11 75 ©2012 JCBN .(12) This questionnaire is composed of 12 questions (Table 2).1* 8. kg/m2 Smoking.05). and 11).5 5. Data are expressed as the mean (SD).6 ± 0. often = 3. 22.1 ± 3.9 ± 21. L FEV 1. Age did not differ among the asthma.1 84. and it was used to determine the prevalence and symptoms of GERD. or hospital. 5.# 27.8 7.5 ± 27. Regular treatments given for COPD patients were budesonide. 7.7 34.9 ± 1.8 ± 10.2 38/2 20.4 ± 12. Comparison of parameters between two groups was done by Student’s t test. % Sputum. Differences in frequency between regurgitation and dysmotility symptoms were assessed by the chi-square test.0 65.9 22/18 23.8 0.1 ± 19.0 5.1 COPD 69.4 19/21 23. Regular treatments given for asthma patients were oral corticosteroids. #Statistically significance between COPD patients and disease control patients.3 9.2 88. 8.0/FVC % pred FEV1. occasionally = 1. pack years Smoking.6 ± 1.7 ± 25.Table 1. oral theophyllines.(6.2 ± 22.0 ± 9. Comparisons among three groups were done by one-way ANOVA with Bonferroni’s multiple comparison test. 0. 9. cur .7 ± 0. % Medication Oral corticosteroids Oral theophyllines Oral expectrants Oral anti histamines Leukotrienes Tulobuterol patches Inhaled steroids Inhaled β2 agonists Inhaled steroids/β2 agonists Inhaled anticholinergics 20 13 2 2 13 9 13 4 17 1 2 15 8 0 0 11 6 4 12 16 99.6*.1 ± 17.4 ± 0.6 6.8 78. or else needed treatment with oral or intravenous corticosteroids at least one episode during the past two years. 5.58 ± 1. leukotrines and inhaled steroids. 5.# 17. The unique feature of the FSSG is that the questions cover both acid regurgitation-related symptoms (questions 1. COPD. Statistics.0 1. % FVC.0*.9 62. Characteristics of asthma. ex .3 ± 2.0. 27 *Statistically significance between asthma patients and COPD patients. COPD. A p value of less than 0. and disease control patients.3164/jcbn.8 ± 2.5 ± 9.7 ± 7. % neutrophil eosiniphil basophil macrophage Pulmonary function %VC. L FEV1.6 ± 11. The body mass index (BMI) of the COPD group was lower than that of the other two groups (p<0.1 1.4 ± 8. and all patients gave informed consent before enrollment.7 ± 22. The cut-off score for diagnosis of GERD was defined as 8 points. Results The characteristics of each group are shown in Table 1. and disease control Asthma Age. 3.0 2. and 12) and gastric dysmotility-related symptoms (questions 2. inhaled steroids/longacting β2 agonists.05 was considered significant. sometimes = 2. 10. 4.8 ± 4. 1 1.3 8. Table 2. The Human Research Committee of Gunma University and the Human Research Committee of Jobu Hospital for Respiratory Disease both approved this study.9 50.0/FVC. Questions of FSSG* Questions q1 q2 q3 q4 q5 q6 q7 q8 q9 Do you get heartburn? Does your stomach get bloated? Does your stomach ever feel heavy after meals? Do you sometimes subconsciously rub your chest with your hand? Do you ever feel sick after meals? Do you get heartburn after meals? Do you have an unusual (e.9 55.7 ± 1. 6.3 65. emergency department. year Sex (male/female) Body mass index.2 ± 13. burning) sensation in your throart? Do you feel full while eating meals? Do some things get stuck when you swallow? q10 Do you get bitter liquid (acid) coming up into your throat? q11 Do you burp a lot? q12 Do you get heartburn if you bend over? *FSSG: The frequency of scale for the symptoms of GERD.g.7 ± 32. which are scored to indicate the frequency of symptoms as follows: never = 170 doi: 10.3 ± 6.2 ± 30.2 2.3* Disease control 65. and always = 4. never Eosinophil of peripheral blood. Comparison of exacerbation number of patients between GERD positive and negative were performed by Fisher’s exact test. 30 3.(18) Exacerbation of asthma and COPD was defined as worsening that required an unscheduled visit to the local doctor.
% Regular use of medication Oral corticosteroids Oral theophyllines Oral expectrants Oral anti histamines Leukotrienes β2 agonist patches Inhaled steroids Inhaled β2 agonists Inhaled steroids/β2 agonists Inhaled anticholinergics 2 6 2 1 4 8 2 0 6 0 0 5 2 0 0 3 6 0 1 8 93.7 ± 2.8 ± 4. Shimizu et al. 5.5.0. and disease control patients (n = 40).3 ± 7.1 ± 8.5 2.5 ± 0.Table 3. some of the patients received inhaled steroid only or inhaled steroid and long acting β2 agonists patches without inhaled anticholinergics because of having glaucoma or dry mouth due to adverse event of anticholinergics.7 ± 3.85* 25.005) and the disease control group (p<0. GERD pt/total pt Age.1 ± 0.76 7.8 2/8 22.9 ± 0. 32. Characteristics of asthma.4 92.05). The number of patients showing predominance of dysmotility-related symptoms was higher in the COPD group than in the asthma group (p<0. 13/40 72.5 ± 5.2 ± 9. J.66 0. 10/40 64. 4. kg/m2 Smoking. 8. The number of patients in each group with a higher score for acid regurgitation symptoms (A>M). Among patients with GERD. 8 *Statistically significance between asthma patients and COPD patients.4 ± 5. the same score for both symptoms (A = M).2 ± 18. The unique feature of the FSSG is that the questions are divided into those covering acid regurgitation-related symptoms (questions 1. 0 0.2 ± 7.3# 2.3 67. When regurgitation. 27. and 11).1 50. 2. 8.9 ± 28.4 33.0 ± 31.9 ± 16. 5.5* 0 1. 3. | March 2012 | vol. % FVC. The prevalence of GERD (detected by the FSSG) was not significantly different among the three groups of asthma patients (10/40.01). 6. Among GERD-positive patients. COPD patients (13/40. ex .1 59.1 ± 7.1* 1. Y. *Significant difference between asthma and COPD. % neutrophils eosiniphils metachromatic cells (basophils) macrophages Pulmonary functions %VC. and 12) and the total score for dysmotility related symptoms (questions 2. #Statistically significance between COPD patients and disease control patients. L FEV 1.1 72. L FEV 1. Nutr. as shown in Table 3. 9. inhaled anticholinergics.0/FVC. cur .3 ± 1. never Eosinophil of peripheral blood. 9. inhaled steroids/long acting β2 agonists.5 4/7 22. Chief symptoms of asthma patients (n = 40). and 12) and those for gastric dysmotility-related symptoms (questions 2. 10.5%). 25%).6 4. pack years Smoking. the COPD patients were older than the asthma and disease control patients (p<0. The total score for acid regurgitation related symptoms (questions 1. 0. year Sex (male/female) Body mass index.and dysmotility-related symptoms were compared among each group.6 0.40 1. 1).93 ± 0.0% pred.1* Disease control 27.5* 4.01) and the disease control group Fig. 7. and 11) were compared. COPD patients (n = 40).1 COPD 32. Of the 13 GERD-positive COPD patients. 11/40 64. 4. or a higher score for dysmotility symptoms (A<M) was determined.29 ± 0. 10.6 28. Biochem.4 ± 1.005) and the disease control group (p<0.5%) and disease control patients (11/40. 50 | no.1 ± 32. the number of patients showing predominance of regurgitation-related symptoms was higher in the asthma group (p<0. oral theophilines.4 81. and disease control having GERD Asthma Frequency of GERD.2 ± 22. 1. 3. the number of patients showing predominance of regurgitationrelated symptoms was higher in the asthma group (p<0. BMI was not statistically different among the groups with GERD. inhaled steroids and β2 agonist patches.3* 52.5. 2 | 171 ©2012 JCBN .8 ± 10.5 0.4 10.5* 13/0* 20. 10 3. 6.9 ± 16. COPD. #Significant difference between COPD and disease controls.1 ± 0.8* 6.0 ± 17. % Sputum. %. % FEV 1. 9.1 ± 34.0. Clin.01) than in the COPD group (Fig. 7.
but the prevalence of GERD in the control group was higher in the present study (32. 10.038* 4.0. *Statistically significance between GERD (+) and GERD (−) patients in COPD. Fig. revealed that hypertension or hyperlipidemia were independent risk factors for GERD and metabolic syndrome patients showed high score of FSSG..e.4% among asthma patients.(21) The prevalence of GERD detected in the present study was similar to that in other studies using the FSSG. COPD patients (n = 13) and disease control patients (n = 11) who were diagnosed as having GERD by the FSSG survey in each group.8 1. The number of patients in each group with a higher score for acid regurgitation symptoms (A>M). #Significant difference between COPD and disease controls. 2. and also this was the one of the reason that no statistical difference in prevalance among asthma. and 12) and the total score for dysmotility related symptoms (questions 2. *Significant difference between asthma and COPD. and 11) were compared. 6. the score for question 7 was higher in asthma patients with GERD having a history of exacerbation during the past 2 years than in asthma patients with GERD without having a history of exacerbation (p<0.25–18. Table 4. or a higher score for dysmotility symptoms (A<M) was examined.11 75 ©2012 JCBN .1 p value OR 95% CI The number of patients having a histrory of disease exacerbations (+) or not having a history of exacerbation (−) were compared in presence of GERD (+) symptoms or without presence of GERD (−) symptoms. healthy versus diseased subjects including those with hypertension and hyperlipidemia.69–13.(20) and that its prevalence was higher among COPD patients (26. 3 a–c).5%). Asthma patients (n = 10). as shown in Fig.01) than in COPD patients with GERD. the mean scores for question 7 (unusual sensation in the throat) was significantly higher in asthma patients and disease control patients with GERD (p<0.05). COPD and control groups in present study. The score for question 2 was higher in COPD patients with GERD having a history of exacerbation of COPD during the past 2 years than in COPD patients with GERD without having a history of exacerbation (p<0. Presence GERD evaluated by FSSG was the risk of COPD exacerbation (OR = 4.69–13. Vertical bars from 0 to 2 show the mean score for each question.05). and disease control patients were diagnosed as having GERD by the FSSG survey in each group. When the scores for each question of patients with GERD were compared among the groups.(22) A possible reason for the different prevalences in the control groups was different background factors.01) (Fig. *Significant difference between asthma and COPD.8.5%) compared with a previous study. 95% CI 0. Associations between exacerbations and presence of GERD symptoms in asthma and COPD patients Exacerbation (+) Asthma GERD (+) Asthma GERD (−) COPD GERD (+) COPD GERD (−) 6 10 8 9 Exacerbation (−) 4 20 5 27 0. Chief symptoms in asthma patients (n = 10). COPD (b). however not in asthma (OR = 3.5 0.25–18. 172 doi: 10. 4. p<0.5% vs 27.01) or the disease control group (p<0.3164/jcbn.01). Also. Fig. while the number with predominance of dysmotility-related symptoms was higher in the COPD group than in the asthma group (p<0. 2. 8. but was not significantly different from asthma patients (Figs. i.5.01) than in the COPD group.01) (Fig. 5.(p<0. COPD patients (n = 13).16 3 0. 4a). 4b). 7. The mean score for question 2 (bloated stomach) was significantly higher in COPD patients than in disease control patients (p<0. Mean score for each FFSG question in asthma (a). 95% CI 1. 9. the same score for both symptoms (A = M). 3.1) (Table 4). and disease control (c) patients with GERD.8%) than among age-matched healthy controls (12. Each data expressed by mean (SD) was shown in Table 5. Data are presented as odds ratios (ORs) and % 95% confidence interval (CI). #Significant difference between COPD and disease controls. The total score for acid regurgitation related symptoms (questions 1. 3.(21) A previous FSSG survey of metabolic syndrome patients. Discussion A previous survey using the FSSG revealed that the prevalence of GER was 27.
2 | 173 ©2012 JCBN .(32) The limitation of this result is that factors of patients in this study might affect the unusual sensation in throat.8) 1. | March 2012 | vol.8) 0.4) 0. the typical symptom detected by the FSSG was an unusual sensation in the throat. there has only been this study about esophageal motility.5) 1. 50 | no.4) 0. There is an increase of tonsillitis.4) Control 1. pharyngitis. The mean scores for questions 2 and question 7 in COPD or asthma patients with GERD having a history of disease exacerbation vs patients without having a history of exacerbation.(6) In present study.5 (0.2 (0.0 (1.1) 1. In COPD patients.3 (1. and presence of GERD evaluated by total score of FSSG was the risk of COPD exacerbations.8) 0. Medications such as β2 agonists and oral theophilines might aggravate GERD. as well as with the severity of hypoxia and bronchial obstruction. allowing it to detect GERD symptoms widely.5 (1.4) COPD with GERD 0. COPD with GERD (n = 13) and disease control with GERD (n = 11).7) 1. It is known that the severity of atrophic gastritis increases with a longer duration of COPD.Table 5. A decrease of lower esophageal sphincter pressure is related to the mechanism of GER in both asthma and COPD patients. A survey using the Rome II criteria for irritable bowel syndrome showed that 14% of COPD patients fulfilled these criteria. such as esophagitis.5 (0.(34) Ventilation affects both gastric mucosal blood flow and gastric mucosal pH.(28) Present study was questionnaire based survey. Scores are compared between COPD patients with GERD having a history vs without having a history of exacerbation.5 (0.4)* 0.(35) Thus. dysmotility of the esophagus has been speculated to have an association with COPD.7 (1. and GERD is also considered to play a role in 55% of hoarseness.1 (0. in addition to acid-reflux-related symptoms. Nutr. In asthma patients. Dysmotility-related symptoms were prominent in the COPD patients.2) 0.2 (1. COPD can influence the mucosa and blood flow of the stomach.0) 1.8 (1.5) 0.2 (0.8) 0.2) 1. and laryngitis among respiratory tract diseases in patients with GERD. As mentioned above. Scores for questions of FSSG on patients with GERD FSSG question number q1 q2 q3 q4 q5 q6 q7 q8 q9 q10 q11 q12 Asthma with GERD 1.9 (1.5 (1.5 (1.(2.8 (0.(33) Eosinophil ratio was actually high in asthma patients. and use of inhaled steroids might have been a cause of “unusual sensation in throat”. Bloated stomach also showed a high score. 4.5 (1.1 (0.7 (0.05. Biochem. and this might affect on unusual sensation in the throat in asthma patients.3) 1. Scores are compared between asthma patients with GERD having a history vs without having a history of exacerbation. Recently published longitudinal study showed that a history of gastroesophageal reflux or heartburn is associated with frequentexacerbation phenotype in COPD patients.2 (0.3 (1. because some sensory nerves from these sites terminate in the same region of the central nervous system. the typical symptom detected by the FSSG was bloated stomach.4) 1.1) 1.0) 1.3) 1. Fig.4) 1. and several patients received oral corticosteroids which indicated those patients were severe asthma.05.8) 0.5 (0. Shimizu et al.1) 1. and each score was indicated mean (SD) in asthma with GERD (n = 10). Asthma patients Y.(23) A physiological study using manometry showed a 35% decrease of peristalsis in COPD patients. Therefore.(24) To our knowledge.9) 0.1 (1. presence of GERD evaluated by total score of FSSG did not affect the asthma exacerbations.4) FSSG was composed by 12 questions (q1 to q12).3) 1.6 (1. COPD patients had more dysmotility symptoms than reflux or heartburn symtoms.2) 1. However. *Significant difference between groups.0) 0. and changes of the mucosal integrity or blood flow may have an effect on GER.(25–27) while dysmotility from the esophagus to intestines seemed to contribute to GER symptoms in COPD.(23) but there has not been enough investigation. Scores of asthma patients with GERD for question 7 (unusual sensation of the throat) (b).2 (1.5) 1. but it was not statistically different from the other items. The FSSG contains questions about dysmotility symptoms.6 (1. and did not include the endoscopic examination.4 (1.5 (0.6 (1. gastric ulcer (GU) and duodenal ulcer (DU).5)# 1. In asthma patients. Therefore it was difficult to discriminate between GERD and FD patients.3 (0. J.8 (0.1 (1.30) Possible mechanisms leading to an unusual sensation in the throat are direct acid reflux or acidic gas reflux. Statistically significance between COPD and disease control is indicated #p<0.0)# 1.(29) Further analysis is needed to proportion of FD in COPD patients.(31) Another mechanism is stimulation of esophageal or laryngeal sensory nerves by gastric acid. Statistically significance between asthma and COPD is indicated *p<0. Dysmotility symptoms are frequently induced by rather functional dyspepsia (FD) than GERD. gastric atrophy or erosive gastroduodnal leisions on endoscopy.2) 0. Rome III consensus for diagnosis of FD needs the absence of organic disorder. The scores of COPD patients with GERD for question 2 (bloated stomach) (a).7 (0. Clin. such as FD. dysmotility to esophagus to intestine possibly affects COPD exacerbation.1) 1. the FSSG was inferior to QUEST for the diagnosis of reflux esophagitis in distinguishing between GERD and other condition.5 (1.7 (1.8) 0.0 (1.8) 0. and there have been no studies of intestinal peristalsis in COPD patients.(36) Patients who had GER symptoms of reflux or heartburn had significantly more hospitalizations related to their COPD.
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The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. 18 Johnson M. gave useful suggestions for the design of this study. and prevention of chronic obstructive pulmonary disease. 17 Saito Y. 327: 891. 130: 1096–1101. 28 Tack J. Effects of bronchial obstruction on lower esophageal sphincter motility and gastroesophageal reflux in patients with asthma. Ventura MT. Author’s Contributions Shimizu Y. Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year. Minnesota. 39: 888–891. Lung function testing: selection of reference values and interpretative strategies. et al. 4 Shimizu Y. 2006. a director of Jobu Hospital. Kusano M. Takayama T. Björnsson E. and wrote the manuscript. and medical staffs of Gunma University and Jobu hospital for assistant the study. MD. 9: 42–45. but the potential effect of anti-reflux therapy. 11 Fass R. Laryngoscope 1991. Nakayama K. 360: 1487–1499. None of the authors have any conflict of interest. et al.had more reflux symptoms than dysmotility symptoms. Kobayashi S. Bisgaard H. 12 Kusano M. (PPIs. Talley NJ. 23 Niklasson A. et al. 16 Carpagnano GE. Castro M. Jibiinkoka 1970. designed the study and collected the datas. 25 Harding SM. National institute of Health. and useful questions from the FSSG were an “unusual sensation in the throat” for asthma patients or “bloated stomach” for COPD patients. et al. Dunitz JM. comparative trial. and Mori M. Review article: supra-oesophageal manifestations of gastrooesophageal reflux disease. Pamer M.37) Multi-drug therapy may be important in asthma and COPD patients with GERD. 26: 1069–1075. 42: 931–934. 104: S33–S38.. BMJ 2003. Bruley des Varannes S. 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